Respiratory syncytial virus (RSV) infects nearly all children by 2 years of age and the leading cause of serious lower respiratory tract disease in young children worldwide. RSV then causes repeat infections that can be serous and life threatening throughout life. It is estimated that RSV leads to 160,000 deaths each year globally and up to 150,000 hospitalizations in the United States in children <5 years of age. The burden of RSV disease has led RSV vaccines are being developed for the young RSV nave child and RSV primed older children and adults. The first RSV vaccine, formalin-inactivated RSV with alum adjuvant (FI-RSV), led to more severe disease with later natural infection. The experience of FI-RSV enhanced disease has generated concern for any non-live virus vaccine in RSV nave children. Therefore, the field has developed live- attenuated vaccines for young children whereas multiple approaches, including inactivated and subunit vaccines, are pursued for RSV primed older children and adults. Despite over 50 years of research, however, no vaccine is available. The failure to develop an effective vaccine suggests that novel approaches and improvements to existing vaccines are needed. The goal of this proposal is to develop G proteins that can be incorporated into existing or new vaccines to improve their safety and efficacy. The rationale for this proposal follows from the fact that 1) natural infection and administration of high titer of RSV neutralizing antibodies provides only partial protection from disease, 2) the G protein induces host responses that contribute to disease, and 3) binding G with antibodies can prevent much of the G-associated disease. The G protein is one of two RSV proteins shown to induce protective immune responses and most vaccines have focused on induced neutralizing antibodies with the F protein. Since antibodies against the central conserved region of G (CCR-G) decrease disease in animals without decreasing virus replication, we hypothesize that G protein constructs specifically designed to increase the level of anti-CCR-G antibodies will eliminate disease enhancing responses and make a vaccine safer and more effective. Since CCR-G is also the most conserved region, it is the region in G best suited to elicit immunity that protects across different RSV strains. The CCR-G does contain amino acid sequences associated with disease but these sequences will be mutated to ensure safety. We propose to make and test a variety of G protein constructs and identify 1 or 2 that induce high titer of anti-CCR-G antibodies, decrease disease with later infection, and can be used in subunit and/or live virus vaccine platforms through two aims: Aim 1: Identify G protein constructs that induce high titers of anti-CCR-G antibodies and decrease disease in RSV-challenged mice after vaccination. Aim 2: Test the vaccine potential of G-modified live RSVs in a mouse model.